Is CDH5 p.Val596Met (c.1786G>A) pathogenic?

CDH5 p.Val596Met (c.1786G>A) is classified Uncertain significance in CDH5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-13). AlphaMissense: likely benign (0.1387); Ultra-rare (popmax 0.0173%, afr).

How common is CDH5 p.Val596Met (c.1786G>A) in the general population?

CDH5 p.Val596Met (c.1786G>A) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about CDH5 p.Val596Met (c.1786G>A)?

AlphaMissense predicts likely benign (score 0.1387) — an in-silico prediction, not a clinical call.

CDH5 p.Val596Met

c.1786G>A · rs146321105 · VCV2286629

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1387 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1387	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.25	donor gain · deltas
Constraint at this position
Conservation	phyloP 0.25	GERP -4, phastCons 0.002
Regional constraint	o/e 0.88	unconstrained · MANE · 24 kb · p 0.00013 · regional, not allelic
Overall
CADD	19.73	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0173% African / African-American · 13/75,072 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00811%

Overall 0.00192% 31/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,775
East Asian	0.00223%	44,886
European (non-Finnish)	0.00136%	73,752
South Asian	0.0011%	91,080

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDH5
Protein: p.Val596Met
Coding: c.1786G>A
MANE Select: NM_001795
dbSNP: rs146321105
Type: single nucleotide variant
Location: chr16:66400965 (GRCh38)
Gene constraint: LOEUF 0.661 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.46

Full CDH5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH5 p.Val266= Benign ★★ same type
CDH5 p.Ala13Ser Uncertain significance ★ ⚠ same type
CDH5 p.Ala187Val Uncertain significance ★ ⚠ same type
CDH5 p.Ala201Ser Uncertain significance ★ ⚠ same type
CDH5 p.Ala21Thr Uncertain significance ★ ⚠ same type
CDH5 p.Ala229Val Uncertain significance ★ ⚠ same type
CDH5 p.Ala353Val Uncertain significance ★ ⚠ same type
CDH5 p.Ala395Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdh5-p-val596met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown